ADAPT78 (RCAN1) is a stress-inducible gene in mammalian cells. It produces a protein (Adapt78) that binds to and inhibits intracellular calcineurin, a phosphatase that mediates many brain cellular responses to calcium. Over the last several years, suggestive evidence has accrued supporting the possible involvement of aberrant ADAPT78 expression in neural disorders. Importantly, overexpression of Adapt78 in brain is observed in both Alzheimer's disease and Down syndrome, and overexpression of an Adapt78 homolog in Drosophila neurons leads to dramatic cognitive impairment. The hypothesis is that Adapt78 overexpression contributes to Alzheimer's and the accelerated dementia observed in Down syndrome patients. This will be tested by using newly generated transgenic mice overexpressing human ADAPT78 in neurons to determine whether neuronal Adapt78 overexpression leads to cognitive impairment over time. In addition, the transgenic mice will be used to determine whether Adapt78 neuronal overexpression alters the levels and activities of proteins thought to be important in learning and memory, including calcineurin-regulated tau, NFAT and CREB as well as MAP kinases and PKA. Morphologically, neurodegeneration, apoptosis, gliosis and Adapt78 aggregate formation will also be evaluated. Combined, it is hoped that these studies will support a role for ADAPT78 (RCAN1) in Alzheimer's disease including the accelerated dementia characteristic of Down syndrome. PUBLIC HEALTH RELEVANCE: Recent evidence suggests that Adapt78, the subject of this proposal, is involved in Alzheimer's disease and the early onset dementia observed in Down syndrome. Alzheimer's disease is the most common of all neurodegenerative disorders, with up to 4.5 million Americans thought to suffer from it, including nearly half of those 85 years of age and older. Down syndrome affects 1 in 800 humans and is the most prevalent genetic-based cause of mental retardation. Our proposed studies, if successful, may provide new insight into Alzheimer's and early onset dementia in Down's patients, and identify a new gene/protein that can be targeted to potentially treat these disorders. Thus, the proposed subject matter has major health relevance.